ABSTRACT Novel immunotherapies for cancer are having a major clinical impact, in particular anti-PD-1 mAbs. However, the mechanisms that explain why a subset of patients responds to these therapies while other patients do not remain incompletely understood. Our preliminary data suggest that a baseline T cell-inflamed tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies. Combination immunotherapies may push clinical efficacy in this subset of patients further. Our over-arching hypothesis is that germline polymorphisms in the host, genomic features of the tumor cells, and the composition of intestinal microbiota profoundly influence the extent of a spontaneous T cell response against a patient's tumor, which in turn will determine the likelihood of response to immunotherapy. Identifying molecular mechanisms for T cell exclusion should point towards new therapeutic interventions that will expand the fraction of patients responding to anti-PD-1- based immunotherapies. While our work to date has focused on melanoma, recent TCGA analysis has indicated that many of the same principles apply to multiple additional cancer types. Thus, a major goal of the proposed funding period will be to broaden our translational research strategy to encompass patients with all cancer types being treated with anti-PD-1- based immunotherapies. The output of this work is therefore anticipated to have profound impact on cancer patient outcomes overall.